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Development of Aggressive Pancreatic Ductal Adenocarcinomas Depends on Granulocyte Colony Stimulating Factor Secretion in Carcinoma Cells.

Pickup MW, Owens P, Gorska AE, Chytil A, Ye F, Shi C, Weaver VM, Kalluri R, Moses HL, Novitskiy SV
Cancer Immunol Res. 2017 5 (9): 718-729

PMID: 28775207 · PMCID: PMC5581681 · DOI:10.1158/2326-6066.CIR-16-0311

The survival rate for pancreatic ductal adenocarcinoma (PDAC) remains low. More therapeutic options to treat this disease are needed, for the current standard of care is ineffective. Using an animal model of aggressive PDAC (Kras/p48), we discovered an effect of TGFβ signaling in regulation of G-CSF secretion in pancreatic epithelium. Elevated concentrations of G-CSF in PDAC promoted differentiation of Ly6G cells from progenitors, stimulated IL10 secretion from myeloid cells, and decreased T-cell proliferation via upregulation of Arg, iNOS, VEGF, IL6, and IL1b from CD11b cells. Deletion of in PDAC cells or use of a G-CSF-blocking antibody decreased tumor growth. Anti-G-CSF treatment in combination with the DNA synthesis inhibitor gemcitabine reduced tumor size, increased the number of infiltrating T cells, and decreased the number of Ly6G cells more effectively than gemcitabine alone. Human analysis of human datasets from The Cancer Genome Atlas and tissue microarrays correlated with observations from our mouse model experiments, especially in patients with grade 1, stage II disease. We propose that in aggressive PDAC, elevated G-CSF contributes to tumor progression through promoting increases in infiltration of neutrophil-like cells with high immunosuppressive activity. Such a mechanism provides an avenue for a neoadjuvant therapeutic approach for this devastating disease. .

©2017 American Association for Cancer Research.

MeSH Terms (16)

Adenocarcinoma Animals Carcinoma, Pancreatic Ductal Cell Proliferation Disease Models, Animal Disease Progression Gene Expression Regulation, Neoplastic Granulocyte Colony-Stimulating Factor Humans Interferon-Stimulated Gene Factor 3, gamma Subunit Mice Mice, Knockout Proto-Oncogene Proteins p21(ras) Signal Transduction T-Lymphocytes Transforming Growth Factor beta

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